Schizophrenia is a severe mental disorder with significant genetic effects. However, the nature and the identity of the genetic factors remain elusive. Recent genome-wide association studies (GWASs) have made substantial progress, identifying several promising candidate genes with common variants. However, these candidates only account for a small proportion of observed heritability. More recently, sequencing and copy number variation (CNV) analyses have documented many rare de novo mutations associated with the risks to this disorder. Combined with what we have learned from GWASs, it is clear that both common and rare variants contribute to genetic risks to schizophrenia. Our current knowledge of schizophrenia is overwhelmingly derived from the study of Caucasian populations. The limited investigations of other ethnicities and the lack of systematic examination of the differences between populations are noticeable in the field. These weaknesses may impede our understanding of the etiology of the disorder. In responding to the request for application AI- 12-021 U.S.-China Program for Biomedical Collaborative Research (R01), we propose studies aiming at the understanding of the genetic architecture of schizophrenia in the Han Chinese population and investigating the shared and ethnic-specific risk factors between the Han Chinese and Caucasian populations. Our aims are: 1. to conduct exome sequencing for 140 nuclear Han Chinese families with multiple affected individuals to discover single nucleotide variations (SNVs) and copy number variations (CNVs) predisposing to the disorder. We plan to use families with both parents (affected or unaffected), 2 affected and 1 unaffected siblings and families with 1 parent, 2 affected and 1 unaffected siblings. The use of families with affected and unaffected siblings allows us to simultaneously discover and characterize transmitted and de novo risk variants. The unaffected siblings in the families are better controls than subjects from the general population, as they can help to distinguish potentially pathological variants from many benign variants observed in the families. 2. To genotype 5,000 cases and 5,000 controls of Han Chinese samples for up to 100 of the most promising risk variants discovered in Aim 1 above to verify their association with SCZ. We will apply a set of sophisticated statistical, bioinformatics and functional filters to select the most promising SNVs. We will focus on those rare variants (including de novo variants) with potential functional consequences and variants occurred at multiple sites in the same genes and biological pathways. 3. To perform comparative analyses using GWAS datasets from both Caucasian and Han Chinese populations to estimate the overlap of genetic risk between the two populations, and to discover and characterize the shared- and ethnic-specific risk genes. We propose to use polygenic analyses to examine the correlation between the PGC and Chinese GWASs to estimate the overlap of risk factors between these populations, and to examine the genetic structure of SCZ in these two ethnic groups.